Frontal lobe syndrome is the hallmark neuropsychiatric response to traumatic brain injury (TBI) in humans. Frontal cortex activity critically involved in "executive" cognitive function is frequently impaired following TBI. There is extensive evidence that dopaminergic lesions of the frontal cortex, innervated by mesocortical dopamine (DA) projects, can lead to persistent cognitive deficits. However, there is a significant gap in the knowledge regarding the mechanisms of frontal lobe syndrome following TBI. The goal of this proposal is to examine the cellular mechanisms of mesocortical dopaminergic deficits after TBI. Specific Aim 1 will examine the relationship between changes in neurochemical and immunohistochemical markers of DA neurotransmission in the dopaminergic ventral tegmental/forebrain systems, at specific time points associated with induction, presence, and recovery of cognitive deficits. Post-traumatic changes in DAergic function may result from alterations in the DA transporter (DAT), a protein that plays a key role in regulating DA neurotransmission by rapidly taking up extracellular dopamine into presynaptic terminals after release. Specific Aim 2 will determine whether DAT levels and/or function are associated with DA neurotransmission deficits following TBI. Specifically, we hypothesize that decreased DAT expression will precede recovery of DAERGIC neurotransmission deficits. Excessive uptake of DA may cause DAergic terminal damage by free radicals generated by autoxidation of DA. Specific Aim 3 will examine this hypothesized mechanism of induction of posttraumatic DAergic deficits. The effects of experimental therapies that either reduce oxidative damage of DA function will also be assessed. Since high extracellular levels of DA and its metabolites are neurotoxic, acute extracellular levels in humans following TBI may be predictive of chronic frontal lobe dysfunction. Specific Aim 4 will determine the relationship between early extracellular levels of DA to neuropsychological outcome measures specific to frontal lobe function in severe TBI patients. This project represents the first systematic examination of the mechanisms of induction and recovery of catecholaminergic-mediated cognitive deficits after TBI. Our long-term goal is to develop new therapies to attenuate the induction and enhance the recovery of neurobehavioral deficits after TBI.